Retinoic acid receptor-related orphan receptors (RORs) are nuclear receptors that are constitutively active and can modulate gene transcription in the absence of binding endogenous ligand. Crystal structures of the ligand binding domain of RORs have found cholesterol and cholesterol sulfate in the ligand binding pocket. It is not clear if these ligands act as modulators or if this finding is an artifact of the purification and crystallization process. More recently, we have shown the oxygenated derivatives of cholesterol, 7-α hydroxycholesterol as an example, are capable of modulating the activity of the RORs. However, it is still unclear if the oxysterols are endogenous ligands for the RORs. It is important to note that this subfamily of nuclear receptors was named not from any known propensity to interact with retinoids, but from sequence homology with retinoic acid receptors (RARs). Recently, it has been found that a high affinity ligand of RORα and RORγ, compound T1317, which was developed previously as a LXR modulator, upon binding to the receptors modulates the receptor's ability to interact with transcriptional cofactor proteins and results in repression of ROR target genes.

Binding of the ligand T1317 was found to repress ROR α/γ dependent transactivation of ROR-responsive reporter genes, and in HepG2 cells reduced the recruitment of steroid receptor coactivator-2 (SRC-2) by RORα at an endogenous ROR target gene. This ligand exhibited a degree of selectivity among this class of nuclear receptors, as it was reported to be inactive versus RORβ. Unlike RORα and RORγ, RORβ appears to not be constitutively active, thus antagonists and inverse agonists have no effect on this receptor's basal activity. However, we have demonstrated that radiolabeled T1317 does in fact bind to RORβ. Thus, in the presence of a yet to be discovered endogenous agonist of RORβ, T1317 and analogs of it, may prove effective at repression this receptor. Likewise, analogs of T1317 that are agonists, or agonists derived from other chemical scaffolds, are likely to be effective at modulating the activity of RORβ. Each of the three major ROR isoforms has multiple variants. See N. Kumar, et al., Mol. Pharm., 77:228-236, 2010. Accordingly, RORs are an attractive target for small molecule drugs useful for therapeutic intervention for metabolic and immune disorders, cancer, and CNS disorders as well as other diseases where the RORs play a role.